The establishment of a critical role of the angiogenic switch in tumorigenesis has made the rationale behind the development of anti-angiogenesis therapy clear (Hanahan & Weinberg 2007). Unfortunately, the ability to attain long-term efficacy of anti-angiogenesis therapy for all cancer-types, in order to reduce cancer to a dormant, chronic manageable disease without increasing morbidity from side effects, has not yet been achieved (Loges et al. 2010, Ferrara 2009, Abdollahi & Folkman 2009, Bergers & Hanahan 2008).
Cumulative observations indicate that all three FDA-approved VEGF pathway inhibitors (anti-VEGFbevacizumab or Avastin, AntiVEGFR2 sunitinib, and sorafanib) result in only transitory improvements in the form of tumor stasis or shrinkage, and only for certain cancers despite most, if not all cancer types exhibiting pathological angiogenesis (Carmeliet 2005; Bergers and Hanahan 2008). Moreover, while anti-VEGF pathway therapies have reduced primary tumor growth and metastasis in preclinical studies (Crawford & Ferrara 2008), recent mouse tumor model studies have reported that sunitinib and an anti-VEGFR2 antibody, DC101, increased metastasis of tumor cells despite inhibition of primary tumor growth and increased overall survival in some cases (Ebos et al. 2009, Paez-Ribes et al. 2009). Addressing this “antiangiogenesis therapy conundrum,” cumulative observations have suggested several mechanisms of evasive and intrinsic resistances (Loges et al. 2010, Ferrara 2009, Abdollahi & Folkman 2009, Bergers & Hanahan 2008) such as: a) activation and/or upregulation of alternative pro angiogenic pathways, b) recruitment of bone marrow-derived pro-angiogenic cells, c) increased pericyte coverage for the tumor vasculature, attenuating the need for VEGF signaling; d) activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization; [for intrinsic resistance]: e) pre-existing multiplicity of redundant pro-angiogenic signals; f) pre-existing inflammatory cell-mediated vascular protection; g) tumor hypovascularity; and h) invasive and metastatic co-option of normal vessels without requisite angiogenesis (Bergers and Hanahan 2008).